Wound healing is a complex and dynamic process that results in the restoration of cellular structures and tissue layers. Generally, the wound healing process can be divided into 3 distinct phases: the inflammatory phase, the proliferative phase, and the remodeling phase. Each of these phases involves a complex and coordinated series of events that includes chemotaxis, phagocytosis, neocollagenesis, collagen degradation, and collagen remodeling.
The recruitment of a variety of specialised cell types to the site of a wound is also a critical part of the process of wound healing. This process requires extracellular matrix and basement membrane deposition, angiogenesis, selective protease activity and re-epithelialisation.
One component of the healing process in mammals is the stimulation of fibroblasts to generate the extracellular matrix. This extracellular matrix constitutes a major component of the connective tissue that develops to repair the wound area.
The actin cytoskeleton is an essential network of filaments found in all cells. Reorganisation of the actin cytoskeleton is central to changes in cell adhesion and motility that underpin wound repair processes. These changes include the lammellipodial crawling of keratinocytes during wound re-epithelialisation, infiltration of inflammatory cells and migration of fibroblasts required for the deposition and remodelling of the extracellular matrix and dermal contraction at the wound site.
Many regulatory proteins influence actin assembly and organisation. For example, members of the gelsolin family of proteins appear to regulate actin filaments by severing pre-existing filaments and/or capping the filament ends. After severing, the proteins remain attached to the “barbed” ends of the broken filament, thereby preventing annealing or addition of actin monomers. Actin filaments are subsequently uncapped by interaction with phosphoinositides, leading to rapid actin assembly. This is the first step in enabling cells to reorientate their cytoskeleton to drive changes in motility, adhesion and contraction.
There is a continuing need to develop methods and medicaments that promote the healing of wounds. For example, it is often desirable to increase the rate of healing in the case of acute wounds (such as penetrative injuries, burns, nerve damage and wounds resulting from elective surgery), chronic wounds (such as diabetic, venous and decubitus ulceration) or for healing wounds in individuals with compromised wound healing capacity, such as the elderly.
However, where the rate of wound healing is increased, there is often an associated increase in scar formation. In most cases, an increase in scar formation is often of secondary importance as compared to the desired increase in the rate of healing. However, there are often instances where the regulation of scar formation is of primary importance and the rate of wound healing is only of secondary consideration. Examples of such situations are scars of the skin where excessive scarring may be detrimental to tissue function and particularly when scar contracture occurs (for instance skin burns and wounds which impair flexibility of a joint). The reduction of scarring to the skin when cosmetic considerations are important is also highly desirable.
There are also a number of diseases, conditions and states in which internal scarring or fibrosis can be highly detrimental. Fibrotic disorders are characterised by the accumulation of fibrous tissue (predominately collagens) in an abnormal fashion within the tissue. Accumulation of such fibrous tissues may result from a variety of disease processes.
Current treatments for wound healing include pressure garments, silicone dressings, and hydrocortisone injections. However, these treatments are empirical, unreliable and unpredictable. There are also no prescription drugs available for the treatment of dermal scarring.
Accordingly, there remains a need to develop new agents and therapeutic strategies that may be used to modulate the healing of wounds, scarring and fibrosis. The present invention arises from the identification that Flightless I, a member of the gelsolin family, is an important mediator of wound repair, and that repair of a wound may be modulated by modulating the activity and/or expression of this protein.
A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was, in Australia or any other country, known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims.